DESCRIPTION: The proposed research focuses on the problem of the preparative-scale separation of racemic mixtures of biochemically important analytes into pure enantiomers. An integrated approach to the two sides of this problem, which are the selectivity and capacity of solid media used for chiral separations, will be pursued. Ultra-high surface area inorganic solids, such as zirconium phosphate, will be intercalated with chiral selector molecules that are capable of binding selectively to a single analyte enantiomer. Prior work has shown that these materials can be intercalated with chiral selectors, and that they have an unprecedented capacity for reversible binding of model analytes. In order to generalize this performance to other biomedically interesting analytes, and to overcome problems associated with host pre-organization effects, combinatorial libraries of cyclophane chiral selectors will be synthesized. These compounds contain an internal binding pocket for molecular analytes that has been shown, with model compounds, to eliminate the expansion of the layered host that attends analyte intercalation. Cyclophane libraries containing short, random oligopeptide sequences will be screened in parallel in order to find the best selector for a given analyte, and the synthesis of these optimized selectors will be scaled up for preparative scale separations. New cyclophane designs containing very strongly pi-accepting pockets will also be developed for molecular analytes that are weak pi-electron donors. In parallel with these studies of molecular design and enantioseparations, the investigator will continue work on the synthesis of a novel class of mesoporous, anionic framework solids. These materials, prepared by the salt-gel method using micellar templates, are promising candidates as host solids that will accommodate larger chiral selector/analyte complexes without pre-organization effects. Chiral molecular interactions play a central role in nearly all life processes. Most biomedically important drugs are chiral, and of those made synthetically, most are sold as racemic mixtures of optic isomers. Generally, only one isomer is therapeutically valuable, and the others may have undesirable side-effects. Recently, new incentives have arisen for re-examining the use of racemic substances as drugs, and for testing new drugs as pure enantiomers. Regulatory agencies now require that the isomeric composition of drugs used in pharmacological testing be known quantitatively. For new drugs and related products, there is growing pressure to carry out pharmacologic, toxicologic, and clinical studies on single optical isomers. Unfortunately, current methods of resolving or synthesizing optically pure compounds on a preparative scale (hundreds of grams to kilograms) do not lend themselves to rapid testing of new substances. The availability of general methods for chiral separations on a preparative scale is essential for individual screening of the optical isomers of new synthetic drugs. The proposed work will develop promising materials for preparative-scale chiral separations.